Nocturnal cardiac autonomic profile in young primary insomniacs and good sleepers

INTPSY-10818; No of Pages 8 International Journal of Psychophysiology xxx (2014) xxx–xxx

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International Journal of Psychophysiology journal homepage: www.elsevier.com/locate/ijpsycho

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Article history: Received 13 May 2014 Received in revised form 24 June 2014 Accepted 26 June 2014 Available online xxxx

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Keywords: Activity Heart rate variability Hyper-arousal Impedance cardiography Insomnia

Department of General Psychology, University of Padua, Italy Center for Health Sciences, SRI International, Menlo Park, CA, USA Brain Function Research Group, School of Physiology, University of the Witwatersrand, Johannesburg, South Africa d Department of Psychology, University of Melbourne, Parkville, Victoria, Australia b c

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We investigated cardiac vagal and sympathetic activity in 13 young primary insomniacs (PI; 24.4 ± 1.6 years) and 14 good sleepers (GS; 23.3 ± 2.5 years) during nocturnal sleep. Pre-ejection period (PEP; inversely related to betaadrenergic sympathetic activity), interval between consecutive R-waves (RR), and vagal-related indices of timeand frequency-domain heart rate variability were computed during pre-sleep wakefulness and undisturbed arousal-free sleep stages (N2, SWS, REM) as well as across the whole night irrespective of the presence of disruptive sleep events (e.g. sleep arousals/awakenings) and/or sleep stage transitions. Groups exhibited a similar vagal activity throughout each undisturbed sleep stage as well as considering the whole night, with a higher modulation during sleep compared to prior wakefulness. However, PEP was constantly shorter (higher sympathetic activity) during pre-sleep wakefulness and each sleep stage in PI compared to GS. Moreover, pre-sleep RR intervals were positively associated with sleep efficiency and negatively associated with wake after sleep onset in PI. Altogether our findings indicated a dysfunctional sympathetic activity but a normal parasympathetic modulation before and during sleep in young adults with insomnia. © 2014 Elsevier B.V. All rights reserved.

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1. Introduction

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Converging data support the link between insomnia and cardiovascular (CV) disease (Spiegelhalder et al., 2010). A growing body of evidence supports the association between insomnia and adverse CV events (Chien et al., 2010; Lanfranchi et al., 2009; Laugsand et al., 2011; Rosekind and Gregory, 2010) and it is well known that overstress of the CV system, i.e. elevated resting blood pressure (Vasan et al., 2001), heart rate (Cooney et al., 2010; Fox et al., 2007), sympathetic hyper-activity (Hamer and Malan, 2010) and autonomic imbalance (Thayer et al., 2010), plays an important role in enhancing the risk for adverse outcomes. Insomnia, therefore, is recognized as a risk factor for developing CV diseases with a risk ratio comparable to the major and well known risk factors such as smoking, hypertension, obesity, and diabetes (Spiegelhalder et al., 2010). Given that insomnia is a major public health problem affecting millions of individuals with a prevalence rate up to 10% in its chronic form (National Institutes of

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Massimiliano de Zambotti a,b,1,2, Nicola Cellini a,2, Fiona C. Baker b,c, Ian M. Colrain b,d, Michela Sarlo a, Luciano Stegagno a

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Nocturnal cardiac autonomic profile in young primary insomniacs and good sleepers

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E-mail addresses: [email protected], [email protected] (M. de Zambotti). 1 SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA. Tel.: +1 650 859 2714x; fax: +1 650 859 2743. 2 Authors contributed equally to the work.

Health (NIH), 2005), it is critical to determine the underlying causes and correlates of CV disease in insomnia. In spite of evidence from epidemiological studies linking insomnia and cardiovascular disease (Lanfranchi et al., 2009; Laugsand et al., 2011; Rosekind and Gregory, 2010; Spiegelhalder et al., 2010), few studies have investigated nighttime autonomic nervous system (ANS) functioning in primary insomniacs (PI). Vagal influence on the heart can be noninvasively assessed by time-domain HRV indices (Camm et al., 1996), like the square root of the mean squared difference of beat-to-beat intervals (RMSSD), the percentage of adjacent beat-to-beat intervals changing N50 ms (pNN50) and frequency-domain heart rate variability (HRV) absolute power in the range of 0.15–0.4 Hz (high frequency, HF). Focusing on the HRV frequency-domain, activity that occurs between 0.04 Hz and 0.15 Hz (low frequency, LF) is still debated, with some studies defining it as a marker of sympathetic activity (see Montano et al., 2009), but others considering it as an index of both sympathetic and parasympathetic modulation (Berntson et al., 1997). However recent reports have challenged this view, considering LF fluctuations being predominantly the expression of vagal activity involved in the control of blood pressure (Billman, 2013; Reyes del Paso et al., 2013). Given this difficulty to determine what exactly the LF reflects, the meaning of the LF/HF ratio, an extensively used index which was supposed to reflect the sympatho-vagal balance (i.e. the balance

http://dx.doi.org/10.1016/j.ijpsycho.2014.06.014 0167-8760/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: de Zambotti, M., et al., Nocturnal cardiac autonomic profile in young primary insomniacs and good sleepers, Int. J. Psychophysiol. (2014), http://dx.doi.org/10.1016/j.ijpsycho.2014.06.014

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Potential participants were recruited through flyers, announcements or advertisements at the Universities of Padua, and evaluated

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2.2. Procedure

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Participants spent two consecutive polysomnographic (PSG) nights (adaptation/screening and experimental) at the sleep laboratory of the University of Padua. Participants were instructed not to drink beverages containing alcohol, caffeine or other stimulants during the 24 h prior to each night. They arrived at the laboratory at the scheduled time (8 pm) and the electrodes were attached. Time in bed was fixed from 12 pm (lights-out) to 8 am (lights-on). The adaptation/screening PSG night confirmed no further sleep disorders. Only data from the experimental nights were analyzed.

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2.3. PSG assessment

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PSG recordings were made with Compumedics Siesta 802 (Compumedics, Abbotsford, Australia) using electroencephalography (EEG), electrooculography and electromyography according to the American Academy of Sleep Medicine (AASM; Iber et al., 2007) guidelines. EEG signals were amplified, band-pass filtered (0.3–35 Hz) and digitalized at 512 Hz. Arousals and stages (Wake, N1, N2, SWS and REM) were scored according to AASM criteria (Iber et al., 2007). Time in bed (TIB; min) was fixed (480 min for all participants). Total sleep time (TST; min), sleep efficiency (SE, as TST / TIB × 100; %), sleep onset latency (SOL, defined as the time from lights-out to the first epoch of sleep; min), rapid-eye-movement latency (REML, defined as the time from the sleep onset to the first epoch of REM, min), wake after sleep onset (WASO, min), the arousal index (ArI, number of arousals times 60 divided by TST), and percentage of time spent in each sleep stage of sleep were calculated.

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by screening interviews to ensure that they met eligibility criteria. PI and NS had to meet, respectively, the Research Diagnostic Criteria for Primary Insomnia and Normal Sleepers (Edinger et al., 2004). More than 100 undergraduates were screened over a period of one year. Thirty insomniacs were potentially eligible. Three of them were excluded for taking hypnotics, 9 for being at risk for depression, and 5 of them had an irregular sleep/wake schedule. Thirteen PI (8 women) and 14 GS (7 women) made up the final sample. PI had to complain of difficulty initiating sleep and/or maintaining sleep, and/or non-restorative sleep. In addition, nocturnal symptoms should impact daytime functioning. Both nocturnal and diurnal symptoms should occur for at least one month and be independent of another medical and/or mental condition. They also had to score ≥ 5 on the Pittsburgh Sleep Quality Index (PSQI) (Buysse et al., 1989) and ≥ 11 on the Insomnia Severity Index (ISI) (Morin, 1993). GS had to report lower scores than these cut-offs, no complaints of unsatisfactory sleep, report a regular sleep/wake schedule and not suffer from any sleep disorders or sleep disruption due to medical and/or mental conditions. Exclusion criteria for both groups were body mass index (BMI; kg m−2) ≥30, extreme chronotypes assessed using the Morningness–Eveningness Questionnaire (MEQ) (Horne and Ostberg, 1976), current medical and/or psychiatric conditions, and shift work or time-zone travel in the six months prior to the study. All participants were non-smokers. The usual average daily consumption was low for alcohol (less than 12 g/day) and caffeine or energetic beverages (less than 200 mg/day) in both PI and GS. No participants reported ever using drugs affecting sleep and/or CV system (e.g. anxiolytics, antidepressants, hypnotics, and benzodiazepines) and all participants were drug free at the time of the experiment. The usual sleep times of participants were similar (±1 h) to the experimental sleep schedule, as assessed by daily sleep diaries completed for one week before the experiment. Participants gave written informed consent. The study protocol was approved by the Ethics Committee of the University of Padua. Demographics and subjective screening measures are provided in Table 1.

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between the two branches of the ANS), has also been debated (Billman, 2011, 2013). Instead of using the controversial LF component of HRV, cardiacsympathetic activity can be non-invasively measured by the preejection period (PEP), a validated impedance cardiography (ICG) index indicating the time of the left ventricular electromechanical systole, controlled by beta-adrenergic mechanisms and inversely related to ANS activity (Schächinger et al., 2001; Sherwood et al., 1990). Notwithstanding these important methodological issues, previous studies employing HRV method reported an overnight increase in LF and reduction in HF power (Bonnet and Arand, 1998), and SDNN (Spiegelhalder et al., 2011) in PI compared to healthy sleepers, suggesting an overall reduced HRV and vagal-related activity in PI. However, others failed to find any group differences in these measures (de Zambotti et al., 2013; Jurysta et al., 2009). Moreover, Varkevisser et al. (2005) failed to find a significant difference in PEP, whereas previous data from our laboratory suggested a constant nocturnal sympathetic hyper-activation (short PEP) during the immediate sleep onset period (de Zambotti et al., 2011) and throughout the whole night in young PI compared to good sleepers (de Zambotti et al., 2013). A recent study performed HRV analysis on selected artifact-free 5min periods sampled across the night in PI and controls (Farina et al., 2014); a single bin was analyzed for each of the following condition: “pre-sleep wake”, “early light sleep”, “slow wave sleep”, “REM sleep”, “early and late N2 sleep”, as well as “post-sleep wake”. PIs had a faster HR but few differences in HRV variables compared to controls: LF power (calculated in normalized units) was increased in pre-sleep wake and LF/HF ratio was elevated in early N2 sleep in PI compared to controls; surprisingly, PI showed an unexpected elevated total and high frequency HRV in early N2 sleep compared to controls. Summarizing, results investigating cardiac ANS functioning in PI are inconsistent. Overall, studies adopting the HRV technique have provided some evidence of a shifting in sympathovagal balance toward sympathetic dominance in PI. However, the analysis of HRV does not allow the possibility of directly assessing the sympathetic modulation of the heart, particularly during sleep when vagal modulation is predominant (Trinder et al., 2012). Other challenging methodological issues contribute to the inconsistencies in findings, including: how periods of analysis for HRV are selected (the presence of arousals/awakenings, and/or sleep stage transitions has not always been considered), the definition of insomnia (ranging from a self-reported definition to a clinical diagnosis, considering or not the presence of objective short sleep duration (see Vgontzas et al., 2013)), and the confounding effect of age and age-related issues on HRV (Antelmi et al., 2004). Here, we aimed to further assess ANS functioning in primary insomniacs and to confirm previous findings of our lab (de Zambotti et al., 2013). To accomplish our aim, we investigated ANS activity in a larger and independent sample of young PI compared with healthy good sleepers (GS) employing frequency- and time-domain HRV analysis and ICG in artifact-free sleep stages determined by polysomnography as well as during the whole night irrespective of sleep stage transitions and disruptive sleep events. Also, we aimed to explore the nocturnal time-course of time-domain vagal-related indices, which are mainly influenced by the circadian system (Burgess et al., 1997), in insomniacs compared to GS. The advantage in combining HRV analysis and ICG allowed us to measure pure indices of vagal (HF power, RMSSD, pNN50) and sympathetic (PEP) activity, together with indices reflecting total HRV (SDNN and total power).

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Please cite this article as: de Zambotti, M., et al., Nocturnal cardiac autonomic profile in young primary insomniacs and good sleepers, Int. J. Psychophysiol. (2014), http://dx.doi.org/10.1016/j.ijpsycho.2014.06.014

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M. de Zambotti et al. / International Journal of Psychophysiology xxx (2014) xxx–xxx t1:1 t1:2

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Table 1 Mean and SD, min and max values for demographic, self-reported and PSG measures. Z and p values of the between groups Mann–Whitney U tests comparisons are displayed.

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24.4 (1.6) 22.7 (2.0) 49.9 (6.5) 2.0 (0.9) 0.9 (1.3)

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23.3 (2.5) 22.8 (2.8) 45.1 (8.2) 10.0 (2.0) 15.8 (3.3) 58.5 (39.9)

20.0 18.4 31.0 7.0 12.0 7.0

28.0 28.0 57.0 13.0 24.0 120.0

1.70 −0.24 1.50 −4.42 −4.42

.089 .808 .132 b.001 b.001

451.25 (18.77) 94.0 (3.9) 22.5 (18.4) 6.2 (4.7) 99 (41) 7.0 (2.7) 6.9 (3.9) 45.6 (5.2) 25.1 (6.0) 22.3 (3.9)

405.5 84.5 1.0 1.5 63 3.7 2.5 39.2 15.1 15.4

476 99.2 72.0 17.5 205 12.3 15 59.6 35.3 31.0

417.93 (40.39) 87.1 (8.4) 45.9 (30.2) 16.2 (16.4) 130 (54) 6.9 (3.0) 6.7 (3.4) 45.4 (7.4) 27.1 (8.1) 20.2 (5.2)

348.5 72.6 7.0 2.5 63 3.8 1.6 32.9 10.9 12.7

464.5 96.8 99.5 56.0 244 14.4 12.3 59.6 40.1 27.4

2.28 2.28 −2.09 −1.94 −2.23 0.05 −0.05 −0.19 0.07 1.74

.023 .023 .034 .052 .026 .961 .961 .846 .627 .382

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PSG data: TST (min) SE (%) WASO (min) SOL (min) REML (min) ArI N1 (%)* N2 (%)* SWS (%)* REM (%)*

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Age (y) BMI (kg m−2) MEQ PSQI ISI Length of Insomnia (months)

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Arousal index (ArI), body mass index (BMI), good sleepers (GS), Insomnia Severity Index (ISI), Morningness Eveningness Questionnaire (MEQ), primary insomniacs (PI), Pittsburgh Sleep Quality Index (PSQI), rapid-eye-movement (REM), REM latency (REML), sleep efficiency (SE), sleep onset latency (SOL), time in bed (TIB; it was fixed for each participants: from midnight to 8 am), total sleep time (TST), and wake after sleep onset (WASO). * = % of TIB.

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Electrocardiogram was assessed with Compumedics Siesta 802 (Compumedics, Abbotsford, Australia) using 1 cm diameter Ag/AgCl electrodes in Lead-II configuration with a sample rate of 512 Hz. Timeand frequency-HRV analyses were performed using dedicated software SRS 5.1 (University of Melbourne, Australia). Frequency-domain measures were calculated by power spectrum analysis applied to the inter-beat-intervals (see Trinder et al., 2001 for details). We calculated: RR (time interval between consecutive R-waves, reflecting frequency of myocardial contraction; ms), total power (reflecting total HRV, ms2), HF (an index of pure vagal tone, absolute power in arbitrary units), HF peak frequency (reflecting respiratory rate, HFpf, Hz), percentage of HF (0.15–0.40 Hz) over total power and LF/HF ratio in arbitrary units. Given that LF is a controversial measure (see Introduction), the latter two indices are reported for descriptive purposes. Using a time domain approach, overall HRV was assessed by calculating the standard deviation of normal-to-normal RR (SDNN, ms) over consecutive 5-min windows; RMSSD (ms) and the pNN50 (%) were calculated as measures of high frequency variability (reflecting vagal activity). The ICG technique was adopted to record PEP (ms), a sympathetic index which correlates well with invasive measures of sympathetic activity (Newlin and Levenson, 1979). The impedance signal was acquired by ICG Minnesota Model 304 B (IFM Ins., Greenwich, CT, USA) using four aluminum bands placed in a tetrapolar configuration with a constant current of 4 mA, 100 KHz. PEP was 30-s ensemble-averaged collected and derived by calculating the time from the onset of the ECG Q-wave (ventricular depolarization) to the dZ/dt B-point (opening of the aortic valve) (see Sherwood et al., 1990). Q and B points were automatically identified on the ensemble-averaged ICG signal by the COP-WIN software (Bio-Impedance Technology, Inc) and manually adjusted when necessary.

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2.5. Data analysis

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For each frequency-domain parameter, 2-min artifact-free windows of undisturbed sleep were selected across the whole night during N2 and SWS and REM sleep following the rules described by Trinder et al. (2001). A 2 min artifact-free eyes-open stable resting wake window (W; before lights-out) was further identified to have a measure of the autonomic base levels preceding the delicate process of falling asleep.

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3. Results

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As expected by the recruiting criteria, self-reported scores of PSQI and ISI were higher (p b .001) in PI compared to GS. PI also had shorter TST, lower SE, more WASO and longer SOL (p = 0.052), indicating poorer sleep quality than GS (Table 1). The analysis highlighted a Stage effect (F(3,75) = 7.95, p b 0.001, ε = 0.57, η2 ρ = 0.50) and a significant interaction Stage × Group (F (3,75) = 3.75, p = 0.046, ε = 0.57, η 2ρ = 0.12) on RR intervals, with a significant lengthening of RR interval during N2 relative to presleep wakefulness for both groups (Fig. 1a). Also, insomniacs showed a lengthening of RR interval for SWS and REM relative to W, but a

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N1 and wake after sleep onset epochs, considered unclear stages, were not analyzed. All periods selected for the analysis were recorded in a lying down position, since posture related variations in preload (the end diastolic volume at the beginning of systole) and afterload (ventricular pressure at the end of systole) could influence PEP values (Houtveen et al., 2005). Time-domain HRV analysis was performed on consecutive 5-min epochs averaged across the whole night irrespective of sleep stage transitions, arousals, or awakenings. Demographic and subjective screening measures and PSG variables were compared between groups with independent t-tests. Repeated measure ANOVAs with Stage (W, N2, SWS, REM) as within-subjects factor and Group (PI and GS) as a between-subjects factor were performed on each frequency-domain HRV variable to assess the effect of stages on autonomic functioning. On each time-domain parameter we performed a repeated measure ANOVA with Time (hours across the night) as within-subjects factor and Group (PI and GS) as a between factor to assess the effect of time on autonomic functioning in the two groups. The Huynh–Feldt correction was applied where sphericity assumption was violated. In these cases, F values, uncorrected degrees of freedom, epsilon values (ε), and corrected probability levels are reported. Tukey's HSD test was used for post-hoc comparisons and partial eta squared (η2p) is reported for effect size. For all the analyses statistical significance was set at p b .05. Lastly, Pearson correlations were run to explore the relationship between pre-sleep wakefulness autonomic measures (RR, HF, and PEP) and objective quality of sleep parameters (SOL, SE, WASO, ArI) separately for each group. HF, LF/HF, and PEP were logarithmically normalized before statistical analysis and the significance level was set at p b .05.

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shortening of RR during REM compared to N2. The PEP showed a main Stage effect (F(3,75) = 10.52, p b 0.001, ε = 0.48, η2ρ = 0.30) due to its lengthening during all sleep stages compared to W (all p's b .01), but also a main Group effect (F(1,25) = 6.10, p = 0.021, η2ρ = 0.20), with a reduced PEP in insomniacs relative to good sleepers (Fig. 1b). The analysis of HF yielded only a main Stage effect (F(3,75) = 15.16, p b 0.001, ε = 0.64, η2ρ = 0.38) with Tukey HSD post-hoc highlighting an increased vagal activity in all sleep stages relative to pre-sleep wakefulness (all p's b .01) and a lower HF power in REM compared to N2 sleep (p = 0.015; Fig. 2a). We found a main Stage effect (F(3,75) = 7.95, p = 0.004, ε = 0.46, η2ρ = 0.24) for TP, with a significant reduction of TP in SWS relative to pre-sleep (p = 0.047), N2 sleep (p = 0.027) and to REM sleep (p b 0.001; Fig. 2b). The LF/HF (Stage effect: F(3,75) = 18.93, p b 0.001, ε = 0.75, η2ρ = 0.43) showed a linear decrease of the ratio from presleep to SWS (p's b 0.001), followed by a strong increase during REM sleep (p's b 0.001, Fig. 2c). Lastly, HFfp did not show any significant differences across stages and groups. Means and standard deviations for the HRV frequency-domain variables and PEP across stages of sleep are provided in Table 2. Time-domain analysis showed a strong circadian influence on vagal-related indices. The RR intervals increase across the night, as highlighted by the significant main effect of Time for RR, F(3,175) = 14.09, p b 0.001, ε = 0.48, η2ρ = 0.36; Fig. 3a). A similar pattern of steady overnight increased was shown by the RMSDD, F(3,175) = 8.18, p b 0.001, ε = 0.37, η2ρ = 0.25; Fig. 3b), and by pNN50. F(3,175) = 8.10, p b 0.001, ε = 0.67, η2ρ = 0.24; Fig. 3c). Interestingly, we found no main effect of Group nor any interaction, indicating no differences in vagal activity between groups across the whole night irrespective of the presence of disruptive sleep events. Also, these results reveal no different circadian influence in the insomnia group relative to good sleepers. Means and standard deviations for the HRV time-domain variables across hours of the night are provided in Table 3.

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Fig. 1. RR intervals (a) and PEP values (b) across stages for insomniacs and good sleepers. Bars are standard errors.

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Fig. 2. High frequency (a), total power (b) and LF/HF ratio (c) across stages for insomniacs and good sleepers. Bars are standard errors.

Correlation analyses highlighted only for the insomniacs a negative association between pre-sleep RR intervals duration and WASO (r = .58, p = 0.038; Fig. 4a), which is reflected also in the positive association between RR and SE% (r = −.61, p = 0.024; Fig. 4b). No significant associations were found for good sleepers.

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4. Discussion

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In the current study we aimed to assess the nocturnal cardiac autonomic activity in young adults with and without insomnia. There is compelling evidence for a strong link between the onset and maintenance of insomnia and a physiological hyper-activity in the sufferers. However, the nocturnal modification of the ANS in this population is under-investigated. In our study, PI sufferers exhibited a shorter PEP (indicating greater sympathetic activity) in arousal-free periods directly before and during sleep. However, groups did not differ in vagal-related

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Please cite this article as: de Zambotti, M., et al., Nocturnal cardiac autonomic profile in young primary insomniacs and good sleepers, Int. J. Psychophysiol. (2014), http://dx.doi.org/10.1016/j.ijpsycho.2014.06.014

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M. de Zambotti et al. / International Journal of Psychophysiology xxx (2014) xxx–xxx Table 2 Mean and SD for the HRV frequency-domain variables and ICG pre-ejection period across stages of sleep in 13 primary insomniacs and 14 good sleepers.

t2:3 t2:4 t2:5 t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14 t2:15

RR (ms)

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PEP (ms) HFna (ms2) LF/HF Total power (ms2) HFpf (Hz)

W Mean (SD)

N2 Mean (SD)

SWS Mean (SD)

REM Mean (SD)

913.80 (142.32) 860.34 (169.26) 98.68 (7.56) 91.23 (17.59) 67.00 (53.89) 69.31 (45.10) 3.53 (3.84) 3.16 (2.47) 1057.46 (1102.12) 756.69 (155.93) 0.27 (0.06) 0.28 (0.06)

978.11 (159.88) 996.88 (164.65) 106.20 (7.71) 96.47 (7.71) 189.91 (140.30) 165.49 (102.52) 1.11 (0.65) 1.17 (0.80) 1014.76 (746.92) 861.09 (488.82) 0.24 (0.03) 0.24 (0.03)

956.98 (165.58) 964.35 (164.64) 104.18 (7.87) 94.78 (7.30) 142.81 (111.78) 132.06 (98.60) 0.86 (0.77) 0.81 (0.58) 601.40 (381.81) 526.34 (317.64) 0.26 (0.03) 0.26 (0.03)

944.61 (163.22) 934.43 (155.93) 106.41 (7.30) 95.92 (11.04) 171.92 (218.73) 102.37 (67–04) 2.51 (1.16) 1.87 (0.86) 1472.25 (1517.95) 857.52 (555.47) 0.24 (0.03) 0.23 (0.03)

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Good sleepers (GS), high frequency (HF; na = narrow absolute, pf = peak frequency), low frequency (LF), primary insomniacs (PI), rapid-eye-movement (REM), slow wave sleep (SWS), and pre-ejection period (PEP).

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indices across the night both when considering the potential impact of disrupted sleep on HRV measures (time-domain analysis) as well as when considering artifact-free epochs of sleep (frequency-domain analysis). Also, time-domain analysis reveals a similar circadian influence in vagal-related indices in both groups. Overall, these results suggest that sympathetic but not vagal modulation of the heart is affected in young PI, which supports most previous studies (de Zambotti et al., 2013; Fang et al., 2008; Jurysta et al., 2009; Varkevisser et al., 2005) and also confirms previous independent findings from our lab (de Zambotti et al., 2011, 2013). Moreover, correlation analyses indicated a positive relationship between pre-sleep RR length and increased sleep quality in PI, suggesting that the elevated pre-sleep cardiac activity that insomniacs experienced could affect their night-time sleep. Despite the elevation in sympathetic activity, RR intervals did not differ significantly between PI and GS during sleep. However, the RR change between pre-sleep wakefulness and all sleep stages was different for PI and GS probably due to a tendency for the RR interval to be shorter in PI during the pre-sleep wake period. Indeed, prior results from our lab found that insomniacs had a significantly shorter RR interval (higher heart rate) in the pre-sleep period, thus showing a greater wake-to-sleep reduction in heart rate than controls during the transition to sleep (de Zambotti et al., 2011). Since heart rate is influenced by both sympathetic and vagal branches of the autonomic nervous system (Cacioppo et al., 2007), we hypothesize that the greater wake-tosleep reduction in heart rate in PI compared to healthy sleepers could be due to an increase in vagal drive to compensate for the elevated sympathetic tone, thus allowing individuals to fall asleep. Further studies are needed to comprehensively investigate this hypothesis. We also analyzed the frequency peak of HF (Brown et al., 1985) in order to control for respiratory rate, which can affect the HRV (Song and Lehrer, 2003). HFfp showed no difference across the stages and between group, and varied within a narrow range in the HF spectrum, between 0.24 and 0.27 Hz, with the greatest difference of about 2 breaths per minute. Thus, the respiratory activity does not seem to play a key role in HRV modulation either in PI or GS (Brown et al., 1985; see also Trinder et al., 2001). However, we cannot completely exclude that PI and GS have no alteration in the cardiopulmonary coupling, as may be detected using measures of coherence (see Thomas et al., 2005). The cardiac autonomic pattern across sleep in good sleepers was consistent with the prior literature. Indeed, similar to our results (see Fig. 1a), in young healthy adults lengthening of RR intervals has been observed during N2 and SWS compared to wakefulness and REM sleep (Bušek et al., 2005; Trinder et al., 2001) with RR showing a gradual lengthening across the night (Bušek et al., 2005; Otzenberger et al., 1997, see Fig. 3a). Also, HF activity rose at sleep onset (Burgess et al., 1999; de Zambotti et al., 2011; Trinder et al., 2001) and remained elevated across the whole sleep period (see Fig. 2a), with a higher vagal modulation during N2 and SWS than REM sleep (Ako et al., 2003;

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Bušek et al., 2005; Elsenbruch et al., 1999; Trinder et al., 2001; Versace et al., 2003), suggesting a vagal predominance during sleep and in particular during NREM sleep stages. A similar pattern was reported for the LF/HF ratio, which is reduced in N2 and SWS compared to wakefulness and markedly increased during REM sleep (Burgess et al., 2004), with a comparable or a higher ratio during REM relative to wakefulness (Ako et al., 2003; Bušek et al., 2005; Elsenbruch et al., 1999, see Fig. 4.2c). Also the strong decrease of TP during SWS (see Fig. 2b) has been previously observed in healthy individuals (Bušek et al., 2005). A limitation of the current study is the small sample size, mainly driven by the low impact of primary insomnia in the general population together with the young age of our participants and the strict inclusion criteria we adopted. However, the sample was well characterized, the methodology was robust, and our data from the GS fit well with prior literature about the nocturnal modulation of ANS activity. The insomniacs in our study followed the well-established pattern of nocturnal vagal activity seen in GS. However, sympathetic activity as measured by PEP differed from GS, highlighting a sympathetic cardiac hyperactivity in young insomniacs. Similarly, others have suggested increased sympathetic hyperactivity during sleep in PI based on HRV measures. However, they have also reported decreased vagal activity during sleep in PI, which we did not find. For example, Bonnet and Arand (1998) reported decreased HF power as well as increased LF power during sleep in insomnia. The authors suggested that this pattern indicated a combination of an increase in sympathetic activity and a reduction in the vagal drive in insomnia. Differences in methodology may explain the discrepant results. Firstly, Bonnet and Arand enrolled participants across a wide age range (18–50 years), whereas our participants were all under the age of 28 years. Age has a major effect on HRV (Antelmi et al., 2004) and could therefore be a confounding factor. Secondly, unlike our sample, the Bonnet and Arand study required potential insomnia patients to meet PSG criteria for poor sleep (SE b 85%). Thirdly, the authors analyzed 5-min windows of ECG data across the night, which could contain sleep stage transitions and arousals, whereas our frequency-domain HRV analysis was conducted on arousal-free 2-min windows. Spiegelhalder et al. (2011) reported night-time significant differences in total HRV but only a trend for decreased vagal HRV indices in insomniacs compared to controls and only when they compared a sub-group of insomniacs with objective poor sleep (SE b 85%). In addition, given the different method adopted by authors to select the epoch for analyses (5-min epochs selected during stage 2 and REM sleep, and a 5-min epoch selected in the pre-sleep waking period with epochs discharged if body movements or artifacts were present for more than 10 s) and the older age of insomnia patients (39.5 ± 11.8 years), it is difficult to conclude if age or disturbed sleep had an effect per se on HRV measures. Moreover, we cannot also exclude that their result of a low vagal activity was driven by an overall suppressed HRV. Finally, Farina et al. (2014) found evidence of increased

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showing psychological arousal during the pre-sleep period in insomniacs. Dysfunctional cognition (e.g. intrusive thoughts, rumination, worry) particularly during the falling asleep process has been considered crucial for the development and maintenance of insomnia especially in light of the efficacy of cognitive behavioral therapies in insomnia

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sympathovagal balance in insomniacs only in “early” Stage 2 sleep suggesting that more than an overall imbalance, the ANS may be more impacted at the beginning of the night. Our findings of increased pre-sleep physiological arousal based on cardiovascular measures (e.g. heart rate) complement those of others

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Fig. 3. Nocturnal temporal profiles of time-domain vagal related indices across hours for insomniacs and good sleepers. Data are 1-h averages of the 8 h from light out (12 am) to light on (8 am). Bars are standard errors.

Please cite this article as: de Zambotti, M., et al., Nocturnal cardiac autonomic profile in young primary insomniacs and good sleepers, Int. J. Psychophysiol. (2014), http://dx.doi.org/10.1016/j.ijpsycho.2014.06.014

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t3:5 t3:6 t3:7 t3:8 t3:9 t3:10 t3:11 t3:12 t3:13 t3:14 t3:15 t3:16 t3:17 t3:18 t3:19 t3:20 t3:21 t3:22 t3:23 t3:24 t3:25 t3:26 t3:27 t3:28

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922.93 (153.35) 920.07 (129.38) 931.21 (127.36) 964.86 (152.80) 957.07 (167.08) 983.64 (178.73) 998.14 (168.35) 975.21 (156.84) 55.63 (24.66) 58.44 (29.13) 61.26 (31.50) 68.50 (34.35) 68.36 (44.56) 74.47 (46.80) 84.53 (55.95) 91.61 (61.28) 28.82 (19.60) 28.42 (19.61) 29.55 (19.43) 34.54 (19.45) 29.71 (21.89) 34.94 (20.86) 36.38 (20.77) 38.66 (20.89)

891.15 (148.75) 914.92 (158.37) 940.85 (157.22) 953.77 (164.41) 961.31 (163.16) 987.46 (152.47) 978.08 (166.26) 970.46 (158.24) 53.15 (19.08) 62.49 (34.19) 60.53 (25.84) 67.62 (30.24) 61.74 (23.07) 66.90 (25.64) 69.65 (29.84) 81.69 (61.28) 28.10 (19.42) 30.12 (21.59) 31.28 (19.31) 34.51 (19.96) 33.95 (18.85) 37.82 (19.65) 36.86 (20.79) 35.30 (20.97)

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treatment (Espie, 2007). Stress and worry have been found to be related to higher HR during wake as well as sleep. Worry, acting to increase CV tone, has been considered a mediator between stress and CV risk (Brosschot et al., 2007).

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Fig. 4. Correlation between pre-sleep RR intervals and WASO (a) and SE (b) in the insomniac group.

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In conclusion, we have shown that young adults with primary insomnia have elevated sympathetic activity in the absence of any difference in vagal activity both directly before sleep and during all sleep stages compared to normal sleepers. Our findings support the role of cardiac autonomic sympathetic hyperarousal in the primary insomnia and may encourage the development of treatments focused on the regulation of this branch of the ANS in insomniacs.

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The role played by the cognitive domain in the relationship between cardiovascular activity and CV risk needs to be further investigated. We cannot exclude the possibility that the overall high CV activation exhibited by insomniacs may be due to the fact that insomniacs are simply more engaged. PEP has been found to respond to environmental conditions that require active coping (see Wright and Gendolla, 2012) whereas coping has been found to be a mediator in the relationship between stress and sleep in insomniacs (Morin et al., 2003). Further, Schmidt et al. (2010) investigating effort mobilization in response to a memory task in young poor sleepers found a positive relationship between blood pressure reactivity to the task and severity of selfreported insomnia suggesting that the severity of insomnia predicts effort mobilization; the authors hypothesized that poor sleepers may recruit extra resources to cope with the everyday cognitive challenges. Mood (Richter and Gendolla, 2009) and fatigue (Wright et al., 2008), both found to impact the responses of the CV system, may further contribute to increase the effort mobilization in insomniacs. Particularly, fatigue seems to have a multifaceted effect on effort depending on task difficulty and perceived importance in accomplishing the task (Wright, 2014). According to this framework, insomniacs may exhibit different levels of activation following different challenges dictated by circumstances more than having an overall constant level of hyperactivation, and these responses may be adaptive rather than being abnormal. Given the homogeneity of our sample due to the young undergraduates recruited, our results are not influenced by BMI and socioeconomic status. We can also exclude the potential effects of smoke, alcohol and caffeine consumption on HRV. Additionally, the narrow and young age range of our subjects can be considered both a strength, allowing us to exclude age and age-related confounders, and also a limitation; our results may not extend to older insomniacs where the severity of insomnia may increase. In our study not all PI met the “conventional” PSG cut-offs for insomnia (SE b 85%; SOL N30; Edinger et al., 2004). However, the diagnosis of insomnia relies solely on a subjective complaint and PSG is not recommended for an insomnia diagnosis (Edinger et al., 2004). Thus, an evaluation of PI based on PSG criteria should be considered an extreme selection of insomnia population and not a standard way to recruit PI (Ohayon, 2002; Zhang and Wing, 2006). Finally, it should be noted that none of our participants suffered from depressive and/or anxiety disorders and did not take medications, which together with “the failure to use state-of-the-art criteria for insomnia diagnosis” have been indicated as the major limitations in investigating the association between insomnia and CV diseases (Spiegelhalder et al., 2010).

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Table 3 Means and standard deviations for the HRV time-domain variables across hours of the night in 13 primary insomniacs and 14 good sleepers.

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